Methotrexate compositions and methods of treatment using same

ABSTRACT

Compositions containing metal salts of methotrexate and methotrexate derivatives or analogs are disclosed. Such compositions comprise a metal salt, preferably a zinc salt, of methotrexate or a methotrexate derivative or analog and a carrier suitable for delivering the metal salt in the desired pharmacological form. Methods of treatment are also disclosed in which such compositions are topically applied or orally or parenterally administered to a patient. The metal salt is present in the treating composition in an amount sufficient to produce the desired therapeutic effect upon application or administration.

This is a continuation of copending application Ser. No. 07/404,424filed on Sep. 8, 1989 now abandoned.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions useful foradministration of therapeutic doses of methotrexate to a patient. Moreparticularly, the present invention relates to the use of metal salts ofmethotrexate and its analogs and derivatives in compositions which areadministered topically or systemically. The zinc salts of methotrexateare most preferred.

BACKGROUND OF THE INVENTION

Methotrexate (also known as MTX;N-(4-[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl) glutamicacid; 4-amino-N-10-methylpteroyl glutamic acid; 4-amino-10-methyl folicacid; methylaminopterin; and amethopterin) is a folic acid analog andantagonist. Methotrexate has been therapeutically employed in numerouschemotherapeutic applications, including the treatment of psoriasis,leukemia, cancers and other disorders resulting from cell proliferation.Methotrexate has also been used as an immunosuppressant and for treatingdermatomyositis and rheumatoid arthritis.

Methotrexate has been shown to demonstrate therapeutic effects whenadministered orally or parenterally. For example, massive doses ofmethotrexate followed by leucovorin rescue are employed in the clinicaltreatment of certain neoplasms [Pratt et al., Cancer Chemother. Rep.Part 3, 6:13 (1975)]. However, when methotrexate is administered inamounts sufficient to produce the desired therapeutic effect, toxicityand other adverse effects have frequently been observed. In this regard,methotrexate has been reported to cause fetal death and/or congenitalanomalies when administered to women of childbearing potential.Hepatotoxicity has also been observed as a result of the administrationof methotrexate, with concomitant elevation in liver enzymes, fattychange, portal inflammation, fibrosis and cirrhosis. Methotrexate hasalso been associated with induced lung disease, bone marrow depression(with associated anemia, leukopenia and/or thrombocytopenia), diarrhea,ulcerative stomatitis and hemorrhagic enteritis.

Orally administered methotrexate has been found to be particularlyeffective for the treatment of psoriasis, a skin disease characterizedby hyperproliferation. However, because of significant systemictoxicity, the use of methotrexate is limited primarily to the mostserious and extensive cases of psoriasis and therefore is of limitedutility when administered by that route. Because of the side effectsassociated with known means of administration of methotrexate,alternative means for administration have been examined. Topicalapplication of methotrexate has been pursued, but has provenunsatisfactory for one reason or another. [see, e.g., Stewart et al.,Arch. Dermatol. 106:357 (1972); Weinstein, Advances in Biology of theSkin, Vol. XII, Pharmacology and the Skin, ed. Montagna et al., pp. 287(Appleton-Century-Crofts, New York 1969); Comaish et al., Arch.Dermatol. 100:99 (1969); Nurse, Arch. Dermatol. 87:258 (1963); Van Scottet al., J. Invest. Dermatol. 33:357 (1959)].

One such reason is that methotrexate is a water-soluble drug and as suchdoes not readily penetrate the stratum corneum, the outermost layer ofthe skin. It also cannot easily penetrate the lower skin layers to reachthe epidermal or other cells upon which it is to act. The hydrophobicstratum corneum layer of the skin acts like a sieve which, probably dueto the water solubility of methotrexate, is impenetrable to more thanvery small amounts of compound. It is likely that this lack ofpenetration into the skin is one of the primary reasons for lack ofefficacy of the drug when applied topically. This is supported by thefinding that direct intralesional administration of methotrexate intopsoriatic plaques, which avoids penetration of the skin, is associatedwith a decrease in mitotic activity and hence a decreased proliferationin the treated area.

Although previous studies have shown that, when topically applied, somemethotrexate trickles through the stratum corneum, the amount passingthrough is far less than the amount originally applied to the skin. As aresult, for topical application of methotrexate to be effective at all,methotrexate must be applied in highly excessive amounts which leads totoxic reactions and other side effects.

Many attempts have been made to increase the percutaneous penetrationand absorption of methotrexate. Most methods involve attempts to alterthe solubility characteristics of methotrexate or the vehicle by whichit is topically applied. For example, McCullough et al. (J. Invest.Dermatol. 66:103 107 (1976)) applied methotrexate in combination withdimethylsulfoxide (80%) or dimethylacetamide (25%) as a vehicle, with noeffect on penetration. Although a 0.1% retinoic acid vehicle did notincrease penetration, a saturated solution of retinoic acid in aqueousethanol produced a marked increase. Decyl methyl sulfoxide (2.5%)produced a 143-fold increase in penetration, which approaches levelssufficient to produce the desired therapeutic effect in lower skinlayers. Lipid soluble methotrexate derivatives (such as the dimethylester of dichloromethotrexate) were also tested and exhibited smallincreases in penetration. Ball et al. (J. Invest. Dermatol. 79:710(1982)) also observed an increase in penetration using "Vehicle N"(alcohol 47.5%, water, laureth 4, isopropyl alcohol 4%, propyleneglycol)from Neutrogena Corporation.

Weinstein et al. [Arch. Dermatol. 25:227 (1989)] reported that a topicalformulation of methotrexate in 1-dodecylazacycloheptan-2-one producedimprovement in psoriatic patients. However, there were no statisticaldifferences in drug treated versus vehicle treated sites one week aftertherapy was discontinued. Enhancement of methotrexate penetration intothe affected skin in patients with psoriasis resulted in emprovement inthe psoriatic plaques with no evidence of systemic side effects.

However, these methods have generally been shown to be disadvantageousin that the solvents used to enhance penetration may not be suitable forhuman use and to do so may present undesirable effects, including skindehydration, irritation of sensitive skin, photosensitivity and changesin the lipid protein structure of the membranes.

Thus, the development of a pharmaceutical composition containingmethotrexate which could be used locally on psoriatic plaques and wouldhave a minimal systemic absorption would be expected to drasticallyreduce the toxicity of methotrexate and increase its utility fortreatment of psoriasis and other disorders. The ability to safely andefficaciously deliver methotrexate into the skin for the treatment ofpsoriasis and other hyperproliferative disorders is a requisite towidespread therapeutic use. To date, conventionally used formulations donot satisfactorily meet these requirements, thus impeding the clinicalutility of methotrexate.

SUMMARY OF THE INVENTION

Thus, it is an object of the present invention to provide forpharmaceutical compositions for the treatment of psoriasis and otherhyperproliferative disorders.

It is yet another object of the present invention to provide safe andefficacious pharmaceutical compositions for the treatment of psoriasisand other hyperproliferative disorders which can be administeredparenterally or orally.

It is yet another object of the present invention to providepharmaceutical compositions for the treatment of psoriasis and otherhyperproliferative disorders which increase absorption and penetrationof methotrexate thereby permitting the use of less methotrexate in thetreatment of a patient.

These and other objects are achieved by pharmaceutical compositionscontaining metal salts of methotrexate, its analogs and derivatives andcompositions containing such metal salts for the treatment of psoriasisand other hyperproliferative diseases of the skin. Although thepharmaceutical compositions according to the invention may beadministered both parenterally and topically, topical application of thecompositions directly to the situs of the hyperproliferative disorder isthe most preferred route of administration.

DETAILED DESCRIPTION OF THE INVENTION

Administration of methotrexate in the form of a metal salt in accordancewith the invention increases absorption and penetration of methotrexate.As compared to prior therapeutic preparations, lower concentrations ofmethotrexate may be employed in such compositions, thereby minimizing oreliminating the toxic effects usually associated with methotrexatetherapy. The pharmaceutical compositions according to the invention aremost effective when applied topically at the site of thehyperproliferative disorder.

The compositions according to the invention comprise a metal salt ofmethotrexate or a methotrexate derivative or analog and a carriersuitable for delivering the metal salt in the desired pharmacologicalform. Any suitable carrier (of which many will be known to skilledartisans) which will incorporate the metal salt at the desiredconcentration and in the desired form can be employed.

The metal salt may include any metal which forms salts with methotrexateincluding without limitation zinc, copper, cadmium and manganese. Thezinc salts are preferred.

Carrier materials include without limitation water, buffers, excipients,binders, fillers, glidants, lubricants, emollients, humectants andsurfactants. Compositions comprising a zinc salt of certain formulaewithout specifically requiring a carrier are also disclosed.

Alternate carriers (excipients) for topical dosage forms include withoutlimitation the following: emollients, such as isopropyl myristate,caprylic/capric triglyceride, PEG-4, PEG-5, PEG-8, PEG-75 lanolin oil,PEG-2 laurate, isopropyl isostearate, isopropyl linoleate, isononylisononanoate, diethyl sebacate, petrolatum, coconut oil, corn oil, oliveoil, palm kernel oil, safflower oil, sunflower oil, glyceryl caprylate,diisopropyl dimerate; surfactants, such as polysorbate 40, polysorbate80, polysorbate 20, ceteth-2, ceteth-20, steareth-2, steareth-21, PPG-15stearyl ether, sorbitan palmitate, sorbitan stearate, sorbitan oleate,sorbitan tristearate, sorbitan trioleate; waxes, such as white wax,cetyl esters wax, spermaceti, cetearyl alcohol, paraffin,microcrystalline wax, PEG-150, PEG-350, carnauba wax, glyceryltribehenate; and humectants, such as sodium lactate, lactic acid,pyrrolidone carboxylic acid, sodium PCA, collagen amino acids, andkeratin amino acids.

Other additives can also be added to the liquid compositions for oraland topical use. Such additives include suspending agents such asacacia, carbomer 934, carboxymethylcellulose sodium, carragenin,gelatin, magnesium aluminum silicate, hydroxypropylcellulose,hydroxyethylcellulose and xanthan gum.

Methods of treatment are also disclosed in which such compositions areorally or parenterally administered or topically applied to a patient.The compositions can be orally administered as a solution, tablet,capsule or other acceptable oral form. Solutions, suspensions and otheracceptable forms can be used for parenteral administration. Embodimentsfor topical application can employ compositions as solutions, lotions,creams, gels or other commonly used topical forms.

The metal salt is present in the treating composition in an amountsufficient to produce the desired therapeutic effect upon application oradministration. When applied topically to an isolated skin site in needof treatment, there is a wide range of amounts of the components whichmay be utilized in the invention. For example, for topical use theformulation preferably contains from about 0.1% to about 10%methotrexate. For systemic administration, it is contemplated that theamount of methotrexate utilized in the composition to treat a patient beless than the known toxic value for methotrexate. Thus, for oral use,the formulation preferably contains between about 0.001 and 50 ugmethotrexate. For parenteral use, concentrations between about 0.1 to 50ug/ml are preferred.

The concentration ranges set forth herein are provided by way ofdescription and not by way of limitation since it is recognized that theconcentration may be adjusted over a wide range depending on a number offactors. Generally, the efficacious amount and concentration of theinhibitors are those which result in the composition exhibiting theproperty or properties required in the treatment for which thecomposition is being used, e.g., psoriasis or actinic keratosis. Thepreferred amounts depend upon the particular condition being treated,the severity of the condition, the method of delivery to the treatmentsite, e.g., topical or systemic, the rate of delivery of the activeingredients to the treatment site, the number of applications of theformulation which can be used, the other inhibitor used, the carriermaterial, etc. Preferred amounts for any specific application may bedetermined by normal pharmacological screening methods used in the art.

Processes for producing such compositions are discussed further below.Other means for combining metal salts with suitable carriers are knownto skilled artisans.

In certain embodiments the zinc salt of methotrexate according to theinvention is of the general formula (I), (II), (III) or (IV): ##STR1##wherein n is 0 or an integer from 1 to 4, X⁻ is an anion (preferablychloride, sulfate, phosphate, nitrate or the anionic form of an organicacid), wherein R2 is hydrogen or an aliphatic, aromatic or arylalkylgroup, and R1 is of general formula (V): ##STR2## wherein R3, R4, R5, R6and R7 are hydrogen or an alkyl group of 1 to 5 carbons.

In the preceding formulae (I)-(V), dotted lines indicate ionic bondsbetween the metal moiety and the connected functional group. Forexample, in formula (I), a single zinc ion is associated with bothcarboxyl groups of one methotrexate molecule. In formula (II), twodifferent zinc ions are associated with the two different carboxylgroups. In formulae (III) and (IV), a single zinc ion is associated withcarboxyl groups on two different methotrexate molecules.

Preferably, the salt is of general formula (III) or (IV) wherein R2, R3,R4, R5 and R6 are hydrogen, and R7 is methyl and n is 2.

Zinc salts of methotrexate can be produced by mixing together an aqueoussolution of a water soluble zinc salt with an aqueous solution of awater soluble salt of methotrexate or with a solution of methotrexate ina water miscible solvent or in a mixture of a water miscible solvent andwater. If a precipitate does not immediately form, the pH is adjusted tobetween 6 and 7 and the precipitated zinc methotrexate is filtered andwashed with water or a water miscible solvent such as alcohol oracetone., and the precipitate is dried.

Another zinc salt of methotrexate of general formula (I) can be producedaccording to the method disclosed in U.S. Pat. No. 4,374,987.

The compositions and methods of the present invention should be usefulfor most indications for methotrexate therapy, including withoutlimitation those previously discussed herein, and also as antibacterial,antiviral and antifungal agents.

The following examples are intended as exemplary and are not intended tolimit the scope of the present invention which is defined by theappended claims.

EXAMPLE 1--PREPARATION OF ZINC SALT

A zinc salt of methotrexate was prepared as follows. Methotrexate (3.0g, 0.0066 moles) was dissolved in 600 ml methanol at room temperaturewith rapid stirring. A solution of zinc acetate (0.6 g, 0.0033 moles) in2 ml methanol was added dropwise to the methotrexate solution. Immediateprecipitation (flocculent) was observed. The mixture was stirred for onehour at room temperature. The mixture was then concentrated in arotating evaporator (roto-vap) at 40° C. The residue obtained (3.2 g)was dried under high vacuum. (C₂₀ H₂₂ N₈ O₅)₂ Zn, MW 974.29; percentzinc: 6.46 (found), 6.71 (theoretical).

EXAMPLE 2--PREPARATION OF ORAL DOSAGE FORM

    ______________________________________                                        Tablet Formula                                                                Ingredient        Percent by Weight                                           ______________________________________                                        Zinc methotrexate 0.001-50.0                                                  Starch, pregelatinized                                                                          10.000-5.0                                                  Microcrystalline cellulose                                                                      10.000-5.0                                                  Lactose           74.899-38.5                                                 Magnesium stearate                                                                              0.100-0.5                                                   Guar gum          5.000-1.0                                                   ______________________________________                                    

The pregelatinized starch, microcrystalline cellulose, lactose,magnesium stearate and guar gum are added to a suitable blender (such asa V-blender) and blended for 15-45 minutes or until the contents havebeen blended uniformly. Zinc methotrexate is added to the above mix andblended to uniformity. This mix is then tabletted in a tableting machinein suitable size die cavities under predetermined pressure to obtainsuitable size tablets. Alternate excipients for making these and otheroral dosage forms include without limitation tribasic calcium phosphate,carboxymethylcellulose sodium, hydroxypropyl methylcellulose,methylcellulose, polyethylene glycol, sodium starch glycolate, sorbitol,compressible sugar and sucrose.

EXAMPLE 3--PREPARATION OF ORAL DOSAGE FORM

    ______________________________________                                        Capsule Formula                                                               Ingredient      Percent by Weight                                             ______________________________________                                        Zinc methotrexate                                                                             0.001-50.0                                                    Lactose         99.984-39.9                                                   Corn starch     0.010-10.0                                                    Magnesium stearate                                                                            0.005-0.1                                                     ______________________________________                                    

The lactose, corn starch and magnesium stearate are added to a suitableblender and blended for 15-45 minutes or until blended uniformly. Zincmethotrexate is added and blended to uniformity. Suitable size hardgelatin capsules are then filled with this mixture with the aid of acapsule filling device. Alternate excipients for making these and otheroral dosage forms include without limitation bentonite, calciumcarbonate, magnesium oxide, magnesium carbonate, talc, silica gel,mannitol, tapioca powder and rice starch. Alternate glidants andlubricants for making these and other oral dosage forms include withoutlimitation metallic stearates such as zinc stearate or calcium stearate;stearic acid; and glycol esters.

EXAMPLE 4--PREPARATION OF CREAMS FOR TOPICAL APPLICATION

    ______________________________________                                               Ingredient  Percent by Weight                                          ______________________________________                                        Phase A: Mineral oil   4.0-7.0                                                         Stearic acid  1.0-4.0                                                         Isopropyl palmitate                                                                         0.5-1.0                                                         Stearyl alcohol                                                                             0.5-1.0                                                         Cetyl alcohol 1.5-2.5                                                         Sorbitan stearate                                                                           0.5-2.5                                                         Polysorbate 60                                                                              0.5-1.0                                                         Synthetic beeswax                                                                           0.5-2.0                                                         Preservative  0.1-0.3                                                Phase B: Water         83.3-37.4                                                       Triethanolamine                                                                             0.3-1.0                                                         Glycerin      2.0-5.0                                                         Preservative  0.1-0.3                                                Phase C: Zinc methotrexate                                                                            0.1-10.0                                                       Triethanolamine                                                                              0.1-10.0                                                       Water          5.0-15.0                                              ______________________________________                                    

Phase (A) ingredients are heated to 75° C. and mixed well. This firstmixture is maintained at 75° C. with continuous agitation The Phase (B)ingredients are mixed and stirred for 15 minutes at 70° C. This secondmixture is maintained at 50° C. with stirring Phase (A) and Phase (B)are combined and stirred for 15 minutes at 70° C. The mixture is thenmaintained at 50° C. with stirring. Phase (C) is made by mixing zincmethotrexate and triethanolamine with stirring until the zincmethotrexate is dissolved and then adding water. Phase (C) is then addedto the mixture of Phase (A) and Phase (B). The mixture is stirred untilhomogeneous then cooled to room temperature with continuous stirring.

EXAMPLE 5--PREPARATION OF LOTIONS FOR TOPICAL APPLICATION

    ______________________________________                                               Ingredient  Percent by Weight                                          ______________________________________                                        Phase A: Isopropyl myristate                                                                         3.0-7.0                                                         Cetyl alcohol 0.4-0.8                                                         Stearic acid  0.6-0.9                                                         Sorbitan laurate                                                                            0.5-1.5                                                         Polysorbate 60                                                                              1.5-3.0                                                         Propylparaben 0.1-0.3                                                Phase B: Water         79.3-47.6                                                       Triethanolamine                                                                             0.3-0.6                                                         Propylene glycol                                                                            4.0-6.0                                                         Methylparaben 0.1-0.3                                                Phase C: Water          0.1-10.0                                                       Triethanolamine                                                                              0.1-10.0                                                       Zinc methotrexate                                                                            0.1-10.0                                              ______________________________________                                    

The Phase (A) ingredients are heated to 70° C. and mixed well. Thetemperature of the mixture is maintained with continuous agitation. ThePhase (B) ingredients are mixed and heated to 70° C. Phase (A) and Phase(B) are mixed and stirred for 15 minutes at 70° C. The mixture is thenmaintained at 50° C. with stirring. Phase (C) is formed by mixing zincmethotrexate and triethanolamine with stirring until zinc methotrexateis dissolved and adding water. Phase (C) is then added to the mixture ofPhase (A) and Phase (B) and stirred until homogeneous. The mixture isthen cooled to room temperature with continuous stirring.

EXAMPLE 6--PREPARATION OF SOLUTIONS FOR TOPICAL APPLICATION

    ______________________________________                                        Ingredient     Percent by Weight                                              ______________________________________                                        Zinc methotrexate                                                                             0.1-10.0                                                      Triethanolamine                                                                               0.1-10.0                                                      Propylene glycol                                                                             1.0-5.0                                                        Preservatives  0.1-0.3                                                        Water          98.7-74.7                                                      ______________________________________                                    

The zinc methotrexate and the triethanolamine are mixed in a suitablecontainer and stirred until the zinc methotrexate is dissolved. Water isthen added to the mixture with stirring. In a separate container, thepreservatives are dissolved in propylene glycol. The propyleneglycol-preservative mixture is then added to the zinc methotrexatesolution and stirred.

From the foregoing it will be apparent to those skilled in the art thatvarious modifications in the above-described compositions and methodscan be made without departing from the scope and spirit of theinvention. Accordingly, the invention may be embodied in other specificforms without departing from the spirit or essential characteristicsthereof Present embodiments, therefore, are to be considered in allrespects as illustrative and not restrictive, the scope of the inventionbeing indicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

We claim:
 1. A composition comprising a pharmaceutically suitablecarrier and a therapeutically effective amount of a compound of thegeneral formula (I), (II), (III) or (IV): ##STR3## wherein n is 0 or aninteger from 1 to 4, M²⁺ is a divalent metal cation, X⁻ is an anion, R₂is hydrogen or an aliphatic, aromatic or arylalkyl group, and R₁ is ofthe general formula ##STR4## wherein R₃, R₄, R₅, R₆ and R₇ are hydrogenor an alkyl group of 1 to 5 carbons.
 2. The composition of claim 1wherein said divalent metal cation is selected from the group consistingof zinc, copper, cadmium and manganese.
 3. The composition of claim 1wherein R₂ is hydrogen, an alkyl, substituted alkyl, alkenyl orcycloalkyl group of 1 to 7 carbons, or a phenyl, benzyl or phenethylgroup of 6 to 10 carbons, wherein the phenyl groups may be optionallysubstituted.
 4. A composition comprising a pharmaceutically suitablecarrier and a therapeutically effective amount of a compound of thegeneral formula (I), (II), (III) or (IV): ##STR5## wherein n is 0 or aninteger from 1 to 4, X⁻ is an anion, R₂ is hydrogen or an aliphatic,aromatic or arylalkyl group, and R₁ is of the general formula (V):##STR6## wherein R₃, R₄, R₅, R₆ and R₇ are hydrogen or an alkyl group of1 to 5 carbons.
 5. The composition of claim 4 wherein said zinc salt isof the general formula (III) or (IV).
 6. The composition of claim 4wherein R₂ is hydrogen, an alkyl, substituted alkyl, alkenyl orcycloalkyl group of 1 to 7 carbons, or a phenyl, benzyl or phenethylgroup of 6 to 10 carbons, wherein the phenyl groups may be optionallysubstituted.
 7. The composition of claim 4 wherein R2, R3, R4, R5 and R6are hydrogen, R7 is methyl and n is
 2. 8. The composition of claim 7wherein said composition is an oral dosage form and said zinc saltconstitutes 0.001 to 50.0 percent by weight of said composition.
 9. Thecomposition of claim 7 wherein said composition is a cream and said zincsalt constitutes 0.1 to 10.0 percent by weight of said composition. 10.The composition of claim 7 wherein said composition is a lotion and saidzinc salt constitutes 0.1 to 10.0 percent by weight of said composition.11. The composition of claim 7 wherein said composition is a solutionand said zinc salt constitutes 0.1 to 10.0 percent by weight of saidcomposition.